Rapamycin-induced inhibition of p34(cdc2) kinase activation is associated with G1/S-phase growth arrest in T lymphocytes

W. G. Morice, G. J. Brunn, G. Wiederrecht, J. J. Siekierka, R. T. Abraham

Research output: Contribution to journalArticle

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Abstract

The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL- 2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1- phase, just prior to entry of the cells into S-phase. In contrast, RAP- treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34(cdc2) kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2- dependent increase in p34(cdc2) kinase activity was blocked by RAP. The RAP sensitivity of the p34(cdc2) activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.

Original languageEnglish
Pages (from-to)3734-3738
Number of pages5
JournalJournal of Biological Chemistry
Volume268
Issue number5
StatePublished - 1 Jan 1993

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T-cells
G1 Phase
Sirolimus
S Phase
Phosphotransferases
Interleukin-2
Chemical activation
T-Lymphocytes
Growth
Tacrolimus Binding Proteins
Interleukin-2 Receptors
Phase Transition
Macrolides
Cell proliferation
Cell Cycle
Phase transitions
Cells
Cell Proliferation
Cell Line

Cite this

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title = "Rapamycin-induced inhibition of p34(cdc2) kinase activation is associated with G1/S-phase growth arrest in T lymphocytes",
abstract = "The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL- 2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1- phase, just prior to entry of the cells into S-phase. In contrast, RAP- treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34(cdc2) kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2- dependent increase in p34(cdc2) kinase activity was blocked by RAP. The RAP sensitivity of the p34(cdc2) activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.",
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Rapamycin-induced inhibition of p34(cdc2) kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. / Morice, W. G.; Brunn, G. J.; Wiederrecht, G.; Siekierka, J. J.; Abraham, R. T.

In: Journal of Biological Chemistry, Vol. 268, No. 5, 01.01.1993, p. 3734-3738.

Research output: Contribution to journalArticle

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